Fungus That Causes Life-Threatening Infections in Persons

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http://www.newswise.com/articles/view/509179/

Source: The Institute for Genomic Research (TIGR) Released: Tue

11-Jan-2005, 10:20 ET

Embargo expired: Thu 13-Jan-2005, 14:00 ET

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Genome of Fungus That Causes Life-Threatening Infections in Persons

With Impaired Immunity

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CRYPTOCOCCUS HIV AIDS FUNGAL INFECTION IMMUNOSUPRESSIVE THERAPY

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Scientists have deciphered the genomes of two closely related

strains of Cryptococcus neoformans, a fungus whose importance as a

human pathogen has risen in parallel with the HIV/AIDS worldwide

epidemic and the increased use of immunosuppressive therapies.

Newswise — In a project that already has benefited an important

field of biomedical research, scientists have deciphered the genomes

of two closely related strains of Cryptococcus neoformans, a fungus

whose importance as a human pathogen has risen in parallel with the

HIV/AIDS worldwide epidemic and the increased use of

immunosuppressive therapies.

The study, posted online January 13 in Science Express, revealed

differences in the virulence strategies used by C. neoformans

compared to other pathogenic fungi. Researchers also examined the

genetic determinants of its pathogenicity by comparing the genomes

of two closely related strains of significantly different virulence.

" Not only have we established a genomic platform for the further

study of this increasingly important pathogen, but the data from the

two strains may provide insight into what determines virulence, "

says n Loftus, a scientist at The Institute for Genomic

Research (TIGR) who is the first author of the Science

paper. " Although the two Cryptococcus strains we examined differ

significantly in virulence, we found surprisingly little difference

in their gene content. "

TIGR scientists led by primary investigator M. Fraser, the

President of TIGR, deciphered the genome of one strain of C.

neoformans while researchers led by Hyman at Stanford

University's Genome Technology Center in Palo Alto, CA, sequenced

the second strain. The project was funded by the National Institute

of Allergy and Infectious Diseases (NIAID), part of the National

Institutes of Health. Numerous collaborators helped to interpret and

analyze the genome sequence data.

C. neoformans, an oval-shaped yeast, is an opportunistic human

pathogen of global importance that is used by researchers as a model

for fungal pathogenesis. Since the 1980s, the number of Cryptococcus

infections has increased sharply – mainly among people with impaired

immunity, including those who have HIV/AIDS or who receive cancer

chemotherapy, steroid treatments, or therapy to prevent rejection of

transplanted organs. One study indicated that as many as 13 percent

of AIDS patients suffer a life-threatening cryptococcal infection at

some point during the course of their HIV disease. The disease

caused by the fungus, cryptococcosis, sometimes involves a fatal

brain inflammation.

" In developing countries, cryptococcosis has emerged as one of the

most common opportunistic infections, and a leading cause of

meningitis and bloodstream infection, " says ph Heitman, a senior

community collaborator on the project who is B. Duke Professor

of Molecular Genetics and Microbiology at the Duke University

Medical Center and an investigator at the Medical

Institute. " In Africa, where both HIV and concomitant cryptococcal

infection are common, survival without therapy is as short as 7 to

10 days following diagnosis. "

The major virulence factor of C. neoformans is its extensive

polysaccharide capsule, an elaborate and dynamic structure

surrounding the cell wall that is unique among fungi that affect

humans. The Science study identified greater than 30 new genes

likely involved in capsule biosynthesis, including a family

containing 7 members of the capsule associated (CAP64) gene.

Researchers compared two closely related genomes of C. neoformans

that differ markedly in their virulence properties. The results

indicate that the differences likely involve other factors than the

absence or presence of individual genes in the two isolates. A

combination of other factors – perhaps including the cumulative

impact of small (single-nucleotide) DNA differences and differences

in when the genes are expressed (turned on or off) – may account for

the disparity in virulence.

Among the surprising findings of the study were the complex gene

structures discovered in C. neoformans that are unlike those found

in previously sequenced yeasts and are reminiscent of the genomes of

more complex organisms. The study also catalogued, for the first

time on a genome-wide scale in fungi, examples of " alternative

splicing " and " antisense " transcripts, in which the gene on one

strand of the DNA differs from the counterpart gene on the opposite

strand. Researchers also identified a high percentage of transposons

(moveable elements) within the genome, which may account for the

genome rearrangements often observed between different Cryptococcus

isolates.

TIGR's Fraser says the Cryptococcus genome sequence will benefit a

wide range of biomedical research into the increasingly significant

human pathogen. Stanford's Hyman says, " The two new Cryoptococcus

genome sequences and their analysis provide many targets for vaccine

development and drug discovery. "

Scientists in the C. neoformans research community – including

Heitman at Duke and Lodge at Saint Louis University (SLU)

School of Medicine – say the project already has given impetus to

biomedical research into fungal infections.

" The genome project has already had a major impact on basic research

of Cryptococcus and will continue to be an enormous factor in the

pace of discovery and in the scope of questions that can be asked

about the basic biology of Cryptococcus as well as the disease

process, " says Lodge, who is SLU's Associate Dean for Research and

who helped coordinate the C. neoformans genome project.

Heitman says, " The genomic sequence and transcriptome analysis are

already proving to be invaluable to researchers working to

understand and cure this infectious disease. " He says the genome

sequence has enabled more rapid gene identification, fueled genome

wide insertional mutagenesis approaches, and provided the foundation

for the development and implementation of a genetic map for

quantitative genetics and population analysis. In addition, the

accuracy of the gene annotation makes it feasible to use

Cryptococcus as a model to study how fungi cause disease. Using the

genomic sequence data, the Cryptococcus research community already

has designed a microarray and has formed a consortium to further

investigate the function of C. neoformans genes.

The sequence data also provides the foundation for a broader genome

project that aims to define the molecular basis for the C.

neoformans species cluster, which includes three related yet

diverged species which differ in virulence attributes, environmental

distribution and which have been diverging over millions of years of

evolution.

This species cluster includes the serotype D strains analyzed in the

Science study, the serotype A variety that is the predominant

pathogenic form of the organism worldwide, and the serotype B

Cryptococcus gattii species that is a primary pathogen and is

currently causing an outbreak on Vancouver Island in British

Columbia. Comparison of the genomes of the three divergent species

promises to reveal in detail the molecular determinants of virulence.

The Institute for Genomic Research (TIGR) is a not-for-profit

research institute based in Rockville, land. TIGR, which

sequenced the first complete genome of a free-living organism in

1995, has been at the forefront of the genomic revolution since the

institute was founded in 1992. TIGR conducts research involving the

structural, functional, and comparative analysis of genomes and gene

products in viruses, bacteria, archaea, and eukaryotes.

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